Uehara Shotaro, Shimizu Makiko, Uno Yasuhiro, Inoue Takashi, Sasaki Erika, Yamazaki Hiroshi
Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, Japan (S.U., M.S., H.Y.); Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Wakayama, Japan (Y.U.); Department of Applied Developmental Biology (T.I.) and Center of Applied Developmental Biology (E.S.), Central Institute for Experimental Animals, Kawasaki, Japan; and Keio Advanced Research Center, Keio University, Minato-ku, Tokyo, Japan (E.S.).
Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, Japan (S.U., M.S., H.Y.); Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Wakayama, Japan (Y.U.); Department of Applied Developmental Biology (T.I.) and Center of Applied Developmental Biology (E.S.), Central Institute for Experimental Animals, Kawasaki, Japan; and Keio Advanced Research Center, Keio University, Minato-ku, Tokyo, Japan (E.S.)
Drug Metab Dispos. 2017 May;45(5):497-500. doi: 10.1124/dmd.117.075184. Epub 2017 Mar 3.
Common marmosets () are potentially primate models for preclinical drug metabolism studies because there are similarities in the molecular characteristics of cytochrome P450 enzymes between this species and humans. However, characterization of non-cytochrome P450 enzymes has not been clarified in marmosets. Here, we report characterization of flavin-containing monooxygenases FMO1-FMO5 identified in marmoset tissues. Marmoset FMO forms shared high amino acid sequence identities (93%-95%) and phylogenetic closeness with human homologous FMO forms. FMO1 and FMO3 mRNA were abundantly expressed in the liver and kidneys among five marmoset tissues examined, where FMO3 protein was detected by immunoblotting. FMO inhibition assays using preheated tissue microsomes indicated that benzydamine -oxygenation and sulindac sulfide -oxygenation in the marmoset liver was mainly catalyzed by FMO3, the major hepatic FMO. Marmoset FMO3 protein heterologously expressed in effectively catalyzed benzydamine -oxygenation and sulindac sulfide -oxygenation comparable to marmoset liver microsomes. These results indicate that the FMO3 enzyme expressed in marmoset livers mainly metabolizes benzydamine and sulindac sulfide (typical human FMO substrates), suggesting its importance for FMO-dependent drug metabolism in marmosets.
普通狨猴（）可能是临床前药物代谢研究的灵长类动物模型，因为该物种与人类细胞色素P450酶的分子特征存在相似性。然而，狨猴中非细胞色素P450酶的特征尚未明确。在此，我们报告了在狨猴组织中鉴定出的含黄素单加氧酶FMO1 - FMO5的特征。狨猴FMO形式与人类同源FMO形式具有高度的氨基酸序列同一性（93% - 95%）和系统发育亲缘关系。在所检测的五种狨猴组织中，FMO1和FMO3 mRNA在肝脏和肾脏中大量表达，通过免疫印迹检测到了FMO3蛋白。使用预热的组织微粒体进行的FMO抑制试验表明，狨猴肝脏中的苄达明 - 氧化和舒林酸硫化物 - 氧化主要由主要的肝脏FMO即FMO3催化。在中异源表达的狨猴FMO3蛋白能够有效地催化苄达明 - 氧化和舒林酸硫化物 - 氧化，其效果与狨猴肝脏微粒体相当。这些结果表明，狨猴肝脏中表达的FMO3酶主要代谢苄达明和舒林酸硫化物（典型的人类FMO底物），表明其在狨猴中FMO依赖性药物代谢中的重要性。
